Several converging lines of evidence support the role of the endogenous opioid system in the reinforcing effects of nicotine; however, the efficacy of opioid antagonists (e.g., naltrexone, NTX) for the treatment of tobacco dependence remains unresolved. The results of clinical studies of NTX for tobacco dependence are inconsistent, which may reflect individual differences in drug response. Rather than concluding that NTX is an ineffective treatment for tobacco dependence, research is needed to identify those smokers for whom NTX will have the strongest beneficial effects on smoking behavior. Therefore, the specific goal of the proposed research is to test whether genetic variation in the functional mu-opioid receptor gene predicts the effects of NTX on cigarette smoking and nicotine reinforcement. Based on preclinical animal and human research, we hypothesize that smokers with the OPRM1 Asp40 variant will be more likely to respond to NTX compared to placebo (PLA), as reflected in reduced cigarette smoking and lower levels of nicotine reinforcement. This hypothesis will be tested using two within-subject behavioral pharmacology paradigms in which NTX 50mg and PLA will be administered to smokers who have been genotyped for OPRM1. The first experiment will examine the effects of NTX on the risk of relapse following an initial smoking lapse, using the validated experimental model of relapse designed by Stitzer and colleagues. Following 3 days of NTX (or PLA) and verified smoking abstinence, 70 smokers (35 from each genotype group) will be exposed to a "programmed" smoking lapse, and then monitored for three days in their natural environments. Following a 5-day wash-out period, the sequence will be repeated with NTX or PLA (order of medications counterbalanced). The primary outcomes are cigarette smoking and nicotine levels following the lapse episode. While such ad-libitum smoking experiments are more naturalistic, these designs can't disentangle the effects of a medication on the reinforcing value of nicotine from effects on the reinforcing value of smoking (including conditioned reinforcers). Therefore, the second experiment will examine the effects of NTX (vs. PLA) on the reinforcing value of nicotine, using a validated cigarette choice paradigm, developed by Perkins and colleagues. In this experiment 80 smokers genotyped for OPRM1 (40 from each genotype group) will receive acute pre-treatment with NTX 50mg or PLA following overnight abstinence, and before they participate in the cigarette choice procedure. The primary outcome will be the number of puffs taken from a 0.6 mg nicotine cigarette versus a 0.05 (denicotinized) cigarette during a 3-hour period. Following a washout period, the sequence will be repeated (with NTX or PLA). The long-term objective of this research is to discover and develop new pharmacogenetic treatment models that can be readily translated to the clinical setting to individualize pharmacotherapy and maximize effectiveness.